Pluronic-Attached Polyamidoamine Dendrimer Conjugates Overcome Drug Resistance in Breast Cancer

Wang, Meng; Li, Ying; Huang-Fu, Ming-Yi; Yi, Xiao; Zhang, Tianyuan; Han, Min; Xu, Dong; Li, Fangyuan; Ling, Daishun; Jin, Yi; J, Gao

doi:10.2217/nnm-2016-0252

Cited by 31 publications

(20 citation statements)

References 41 publications

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“…Dendrimers 17,18 are hyperbranched, monodispersed macromolecules that have shown significant potential in gene delivery, 19,20 drug delivery, 20-22 imaging, 23 and numerous other applications related to nanomedicine. 24 Dendrimers offer unique physicochemical features such as (1) highly defined monodisperse structure, (2) nanometer size range, (3) multivalency, and (4) easy tuneability.…”

Section: Introductionmentioning

confidence: 99%

Activated Microglia Targeting Dendrimer–Minocycline Conjugate as Therapeutics for Neuroinflammation

et al. 2017

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Brain-related disorders have outmatched cancer and cardiovascular diseases worldwide as the leading cause of morbidity and mortality. The lack of effective therapies and the relatively dry central nervous system (CNS) drug pipeline pose formidable challenge. Superior, targeted delivery of current clinically approved drugs may offer significant potential. Minocycline has shown promise for the treatment of neurological diseases owing to its ability to penetrate the blood–brain barrier (BBB) and potency. Despite its potential in the clinic and in preclinical models, the high doses needed to affect a positive therapeutic response have led to side effects. Targeted delivery of minocycline to the injured site and injured cells in the brain can be highly beneficial. Systemically administered hydroxyl poly(amidoamine) (PAMAM) generation-6 (G6) dendrimers have a longer blood circulation time and have been shown to cross the impaired BBB. We have successfully prepared and characterized the in vitro efficacy and in vivo targeting ability of hydroxyl-G6 PAMAM dendrimer–9-amino-minocycline conjugate (D-mino). Minocycline is a challenging drug to carry out chemical transformations due to its inherent instability. We used a combination of a highly efficient and mild copper catalyzed azide–alkyne click reaction (CuAAC) along with microwave energy to conjugate 9-amino-minocycline (mino) to the dendrimer surface via enzyme responsive linkages. D-mino was further evaluated for anti-inflammatory and antioxidant activity in lipopolysaccharides-activated murine microglial cells. D-mino conjugates enhanced the intracellular availability of the drug due to their rapid uptake, suppressed inflammatory cytokine tumor necrosis factor α (TNF-α) production, and reduced oxidative stress by suppressing nitric oxide production, all significantly better than the free drug. Fluorescently labeled dendrimer conjugate (Cy5–D-mino) was systematically administered (intravenous, 55 mg/kg) on postnatal day 1 to rabbit kits with a clinically relevant phenotype of cerebral palsy. The in vivo imaging study indicates that Cy5–D-mino crossed the impaired blood–brain barrier and co-localized with activated microglia at the periventricular white matter areas, including the corpus callosum and the angle of the lateral ventricle, with significant implications for positive therapeutic outcomes. The enhanced efficacy of D-mino, when combined with the inherent neuroinflammation-targeting capability of the PAMAM dendrimers, may provide new opportunities for targeted drug delivery to treat neurological disorders.

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Section: Introductionmentioning

confidence: 99%

Activated Microglia Targeting Dendrimer–Minocycline Conjugate as Therapeutics for Neuroinflammation

et al. 2017

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“…Treatment with PAMAM‐paclitaxel is significantly more potent than with paclitaxel in inhibiting the proliferation of esophageal, gastric, and pancreatic cancer cell lines. Besides, compared to paclitaxel, treatment with PAMAM‐paclitaxel induces higher expression of P53 and P21 pro‐apoptotic proteins in AGS gastric cancer cell lines . Maltose‐modified poly (propylene imine) glycodendrimers (PPI‐m OS) loaded with cytarabine increase the drug cytotoxicity and apoptosis in 1301 and HL‐60 leukemic cell lines.…”

Section: Novel Strategies Against Mdrmentioning

confidence: 99%

“…Besides, compared to paclitaxel, treatment with PAMAM-paclitaxel induces higher expression of P53 and P21 pro-apoptotic proteins in AGS gastric cancer cell lines. 59 Maltose-modified poly (propylene imine) glycodendrimers (PPI-m OS) loaded with cytarabine increase the drug cytotoxicity and apoptosis in 1301 and HL-60 leukemic cell lines. In addition, through a significant increase in the cellular uptake of cytarabine by tumor cells, it is suggested that this delivery system is a versatile candidate overcoming MDR in resistant acute lymphoblastic leukemia cells with lower expression of hENT1.…”

Section: Dendrimersmentioning

confidence: 99%

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons

Majidinia

Mirza-Aghazadeh-Attari

Rahimi

et al. 2020

IUBMB Life

120

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Multidrug resistance (MDR), defined as the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, is an important barrier in treating malignancies. Initially, it was discovered that cellular pumps dependent on ATP were the cause of resistance to chemotherapy, and further studies have found that other mechanisms such as increased metabolism of drugs, decreased drug entry, and defective apoptotic pathways are involved in this process. MDR has been the focus of numerous initiatives and countless studies have been undertaken to better understand MDR and formulate strategies to overcome its effects. The current review highlights various nano‐drug delivery systems including polymeric/solid lipid/mesoporous silica/metal nanoparticles, dendrimers, liposomes, micelles, and nanostructured lipid carriers to overcome the mechanism of MDR. Nanoparticles are novel gateways to enhance the therapeutic efficacy of anticancer agents at the target site of action due to their tumor‐targeting abilities, which can limit the unwanted systemic effects of chemotherapy agents and also reduce drug resistance. Additionally, other innovative strategies including RNA interference as a biological process used to inhibit or silence specific gene expression, natural products as MDR modulators with little systemic toxic effects, which interfere with the functions of proteins involved in drug efflux, and physical approaches such as combination of conventional drug administration with thermal/ultrasound/photodynamic strategies are also highlighted.

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“…Dendrimers are most commonly derived from polyamidoamine, affording a hydrophilic delivery system. Although no clinical data are available, a pluronic‐attached polyamidoamine dendrimer conjugates for doxorubicin successfully overcame multidrug resistance in both in vitro and in vivo breast cancer models . Furthermore, a folate receptor‐targeted dendrimer loaded with a small interfering RNA and cis‐diamine platinum exhibited enhanced therapeutic efficacy in vitro for lung cancer .…”

Section: Emerging Therapeutic Drug‐delivery Strategies For Lrrmentioning

confidence: 99%

“…Although no clinical data are available, a pluronic-attached polyamidoamine dendrimer conjugates for doxorubicin successfully overcame multidrug resistance in both in vitro and in vivo breast cancer models. 120 Furthermore, a folate receptor-targeted dendrimer loaded with a small interfering RNA and cis-diamine platinum exhibited enhanced therapeutic efficacy in vitro for lung cancer. 121 Although dendrimers are typically formulated for intravenous delivery, they can also be made in aerosol formulations, providing potential for targeted lung delivery.…”

Section: Peritoneal Surface Malignanciesmentioning

confidence: 99%

Local Cancer Recurrence: The Realities, Challenges, and Opportunities for New Therapies

Mahvi

Liu

Grinstaff

et al. 2018

CA A Cancer J Clinicians

248

167

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Locoregional recurrence negatively impacts both long-term survival and quality of life for a number of malignancies. For appropriate-risk patients with an isolated, resectable local recurrence, surgery represents the only potentially curative therapy. However, oncologic outcomes remain inferior for patients with locally recurrent disease even after macroscopically complete resection. Unfortunately, these operations are often extensive with significant perioperative morbidity and mortality. This review highlights selected malignancies (mesothelioma, sarcoma, lung cancer, breast cancer, rectal cancer, peritoneal surface malignancies) in which surgical resection is a key treatment modality and where local recurrence plays a significant role in overall oncologic outcome with regards to survival and quality of life. For each type of cancer, the current, state-of-the-art treatment strategies and their outcomes are assessed. The need for additional therapeutic options is presented given the limitations of the current standard therapies. New and emerging treatment modalities, including polymer films and nanoparticles, are highlighted as potential future solutions for both prevention and treatment of locally recurrent cancers. Finally, we identify additional clinical and research opportunities, and propose future research strategies based on the varying patterns of local recurrence among the different cancers.

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Pluronic-Attached Polyamidoamine Dendrimer Conjugates Overcome Drug Resistance in Breast Cancer

Abstract: With optimized PF68 modification, PAMAM-PF68 conjugates can significantly overcome multidrug resistance in vitro and in vivo.

Cited by 31 publications

References 41 publications

Activated Microglia Targeting Dendrimer–Minocycline Conjugate as Therapeutics for Neuroinflammation

Activated Microglia Targeting Dendrimer–Minocycline Conjugate as Therapeutics for Neuroinflammation

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons

Local Cancer Recurrence: The Realities, Challenges, and Opportunities for New Therapies

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